This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhat, H. K. Articles by Brass, E. P. Search for Related Content PubMed PubMed Citation Articles by Bhat, H. K. Articles by Brass, E. P. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Peripheral Arterial Disease Related Collections Biochemistry and metabolism Clinical genetics Peripheral vascular disease

(Circulation. 1999;99:807-812.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Skeletal Muscle Mitochondrial DNA Injury in Patients With Unilateral Peripheral Arterial Disease

Hari K. Bhat, PhD; William R. Hiatt, MD; Charles L. Hoppel, MD; Eric P. Brass, MD, PhD

From the Department of Medicine, Harbor-UCLA Medical Center (H.K.B., E.P.B.), Torrance, Calif; University of Colorado Health Sciences Center (W.R.H.), Denver, Colo, and Cleveland VA Medical Center (C.L.H.), Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, Ohio.

Correspondence to Eric P. Brass, MD, PhD, Department of Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA 90509. E-mail ebrass{at}ucla.edu

Background—Patients with peripheral arterial disease (PAD) have exercise limitation due to claudication-limited pain and metabolic alterations in skeletal muscle. PAD is also associated with oxidative stress, which is a known cause of mitochondrial DNA (mtDNA) injury. The present study was designed to test the hypothesis that PAD is associated with mtDNA injury, as reflected by an increased frequency of a specific 4977–base pair (bp) mtDNA deletion mutation.

Methods and Results—The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subjects with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increased deletion frequency and the hemodynamically affected (worse affected) PAD limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse-affected limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA content, citrate synthase activity, and cytochrome c oxidase activity were not different in the muscle from the 3 limb populations. However, the ratio of citrate synthase to cytochrome c oxidase was higher in the worse- versus less-affected limbs of PAD patients.

Conclusions—The present study demonstrates a large increase in the frequency of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.

Key Words: peripheral vascular disease • aging • metabolism

This article has been cited by other articles:

				I. I. Pipinos, A. R. Judge, J. T. Selsby, Zhen Zhu, S. A. Swanson, A. A. Nella, and S. L. Dodd Basic Science Review: The Myopathy of Peripheral Arterial Occlusive Disease: Part 2. Oxidative Stress, Neuropathy, and Shift in Muscle Fiber Type Vascular and Endovascular Surgery, May 1, 2008; 42(2): 101 - 112. [Abstract] [PDF]

				D. C. Isbell, S. S. Berr, A. Y. Toledano, F. H. Epstein, C. H. Meyer, W. J. Rogers, N. L. Harthun, K. D. Hagspiel, A. Weltman, and C. M. Kramer Delayed Calf Muscle Phosphocreatine Recovery After Exercise Identifies Peripheral Arterial Disease J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2289 - 2295. [Abstract] [Full Text] [PDF]

				E. P Brass, W. R Hiatt, and S. Green Skeletal muscle metabolic changes in peripheral arterial disease contribute to exercise intolerance: a point-counterpoint discussion Vascular Medicine, November 1, 2004; 9(4): 293 - 301. [Abstract] [PDF]

				L.-P. Lai, C.-C. Tsai, M.-J. Su, J.-L. Lin, Y.-S. Chen, Y.-Z. Tseng, and S. K. S. Huang Atrial Fibrillation Is Associated With Accumulation of Aging-Related Common Type Mitochondrial DNA Deletion Mutation in Human Atrial Tissue Chest, February 1, 2003; 123(2): 539 - 544. [Abstract] [Full Text] [PDF]

				K. Yamagata, K. Muro, J. Usui, M. Hagiwara, H. Kai, Y. Arakawa, Y. Shimizu, C. Tomida, K. Hirayama, M. Kobayashi, et al. Mitochondrial DNA Mutations in Focal Segmental Glomerulosclerosis Lesions J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1816 - 1823. [Abstract] [Full Text] [PDF]

				P. Cerretelli and B. Grassi Gas Exchange, MRS and NIRS Assessment of Metabolic Transients in Skeletal Muscle Integr. Comp. Biol., April 1, 2001; 41(2): 229 - 246. [Abstract] [Full Text] [PDF]

				E. P. Brass, W. R. Hiatt, A. W. Gardner, and C. L. Hoppel Decreased NADH dehydrogenase and ubiquinol-cytochrome c oxidoreductase in peripheral arterial disease Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H603 - H609. [Abstract] [Full Text] [PDF]

				E. P Brass, H. Wang, and W. R Hiatt Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease Vascular Medicine, November 1, 2000; 5(4): 225 - 230. [Abstract] [PDF]

				E. P Brass and W. R Hiatt Acquired skeletal muscle metabolic myopathy in atherosclerotic peripheral arterial disease Vascular Medicine, February 1, 2000; 5(1): 55 - 59. [Abstract] [PDF]

				T. A. Bauer, J. G. Regensteiner, E. P. Brass, and W. R. Hiatt Oxygen uptake kinetics during exercise are slowed in patients with peripheral arterial disease J Appl Physiol, August 1, 1999; 87(2): 809 - 816. [Abstract] [Full Text] [PDF]